The RNA-binding protein HuR is a posttranscriptional on switch for CD4+ Th2 and Th17 differentiation (LYM3P.730)

Abstract

Abstract Posttranscriptional control by RNA binding proteins (RBPs) in CD4+ T cells is poorly understood. The RBP, HuR, regulates IL-4, IL-13 and GATA-3, by binding to AU-rich (ARE) regions in their 3’ UTRs. We hypothesized HuR is regulating CD4+ Th2 differentiation by controlling mRNA stability. We previously showed that HuR over-expression results in increased Th2 differentiation and Th2 cytokines. We generated a new model to study Th2 differentiation, distal Lck-cre ROSA HuRfl/fl, in which HuR is ablated prior to T cell activation. This resulted in profound suppression of Th2 but not Th1 cytokines, under in vitro conditions. We used the ova challenge model of airway inflammation to study antigen presentation and in vivo cytokine regulation. HuR KO mice had completely abolished lung cellular inflammation to levels similar to non-immunized mice. This further resulted in significant reductions in IL-4, IL-13 secretion, and serum IgE levels. We also investigated effects of HuR ablation in Th17 differentiation. We show HuR regulates IL-17 expression by controlling transcript stability. HuR KO T cells have greatly reduced Th17 differentiation (66% reduction) and diminished onset and severity of inflammation in an EAE model. These data indicate that HuR is required for efficient CD4+ Th2 and Th17 differentiation both in vitro and in vivo but not Th1. These findings reveal nuanced control by HuR upon different CD4+ T cell subsets.